Patients with ulcerative colitis (UC) are at increased risk for development of colorectal cancer. Mechanisms of carcinogenesis in this high-risk population, however, remain poorly understood. For this reason, progress in the development of optimal detection and chemoprevention of precancerous lesions has been limited. This proposal will use novel methods combining molecular biology, genomic data, and bioinformatics in order to provide new insights into an area where there is a substantial gap in our knowledge. Success in these studies could greatly advance the current standard of care in inflammatory bowel disease (IBD). The broad objective of this proposal is to test the hypothesis that miR-31, miR-34a, and miR-106b contribute to the development of neoplasia in chronic ulcerative colitis (UC). We further postulate that derangements in pathways involving these miRNAs can be reversed by vitamin D. If successful, this proposal will identify new targets that could improve detection o neoplasia and suggest more effective chemopreventive strategies in IBD. To this end, I propose three specific aims: 1) Determine if mucosal changes in miR-31, miR-34a, and miR-106b precede the development of dysplasia in patients with chronic UC; 2) Identify field effects of key genomic pathways involving miR-31, miR-34a, and miR-106b associated with remote neoplasia in UC; and 3) Investigate the effects of chemopreventive vitamin D on key miRNA-mRNA pathways involving miR-31, miR-34a, and miR- 106b implicated in IBD-cancer. I seek to develop a career as an independent translational gastroenterologist focusing on genomics in inflammatory bowel disease. My long-term research goals are to utilize genomic studies in order to understand mechanisms of carcinogenesis and identify targets for detection and chemoprevention of neoplasia in patients with IBD. My career goals necessitate additional training in genomics and cancer biology. The 5-year career development program outlined in this application will take place at the University of Chicago, which has attained distinction in th clinical care and research of IBD, cancer biology, and genomics and systems biology. Dr. Marc Bissonnette, Associate Professor of Medicine, is my mentor and will provide expertise and guidance in colon cancer biology. Dr. Eugene Chang, Professor of Medicine, is a co-mentor and will provide expertise in molecular aspects of IBD. An inter-disciplinary Advisory Committee comprised of distinguished researchers will provide guidance for me during this development period. This committee is comprised of Dr. Aaron Dinner, an expert in bioinformatics, Dr. John Kwon, an NIH funded physician-scientist with expertise in miRNAs, and Dr. David Rubin, an expert in clinical inflammatory bowel disease research. With the mentorship, education, training, and resources available to me, I will be uniquely equipped to undertake independent translational genomic and systems biology research focused in IBD by the completion of this career development award. PUBLIC HEALTH RELEVANCE: The prevalence of inflammatory bowel disease (IBD) is increasing worldwide, and patients with IBD are at increased risk for the development of cancer. Because there are significant gaps in scientific knowledge as to why cancer develops in this high-risk population, prior efforts to prevent precancerous lesions have been generally unsuccessful. The goal of this proposal is to provide valuable insights into the biology of cancer in IBD, which may improve detection and lead to targeted therapies to prevent the development of cancer.